Mutations, Bottlenecks, and Clonal Sweeps: How Environmental Carcinogens and Genomic Changes Shape Clonal Evolution during Tumor Progression

Abstract

The transition from a single, initiated cell to a full-blown malignant tumor involves significant genomic evolution. Exposure to carcinogens—whether directly mutagenic or not—can drive progression toward malignancy, as can stochastic acquisition of cancer-promoting genetic events. Mouse models using both carcinogens and germline genetic manipulations have enabled precise inquiry into the evolutionary dynamics that take place as a tumor progresses from benign to malignant to metastatic stages. Tumor progression is characterized by changes in somatic point mutations and copy-number alterations, even though any single tumor can itself have a high or low burden of genomic alterations. Further, lineage-tracing, single-cell analyses and CRISPR barcoding have revealed the distinct clonal dynamics within benign and malignant tumors. Application of these tools in a range of mouse models can shed unique light on the patterns of clonal evolution that take place in both mouse and human tumors.